The use of purine and pyrimidine derivatives as anti-viral compounds is known. For example, U.S. Pat. No. 4,27,025 discloses 8-azapurine derivatives, such as 9-(2-hydroxyethoxymethyl)-8-azaguanine and 9-(2-benzoyloxyethoxymethyl)-8-azaguanine, as anti-viral compounds. U.S. Pat. No. 4,146,715 discloses 2-amido-9-(2-acyloxyethoxymethyl)hypoxanthines and U.S. Pat. No. 4,199,574 discloses that 9-(2-hydroxyethoxymethyl) and related derivatives of certain 6-, and 2,6-substituted purines have anti-viral activity. U.S. Pat. Nos. 4,347,360 and 4,355,032 disclose that 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (gancyclovir) has anti-viral activity and Colla et al., J. Med. Chem., 26, 602-604 (1983) and published European Patent Application No. 95 813 disclose esters and ethers of acyclovir. European Patent Application Publication No. 85 424 discloses acyl derivatives of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, and U.S. Pat. No. 4,617,304 discloses thymidine kinase substrates having a 3-membered cycloalkyl group in the side chain of a purin-9-yl or pyrimidin-1-yl derivative.
U.S. Pat. No. 4,424,211 discloses antiviral activity for (E)-5-(2-bromovinyl)-2-deoxyuridine (BVDU) and related compounds, with esters of BVDU having antiviral activity being disclosed in published EPO application No. 97 039. PCT International Application No. WO 84 00,759 discloses antiviral activity for 5-(2-chloroethyl)-2'-deoxyuridine (CEDU) and related compounds.
Inhibition of herpes simplex type I (HSV-1) thymidine kinase by certain 9-(hydroxyalkyl)- and 9-(hydroxyalkenyl)guanines has been disclosed in published EPO Application 146 516, but the antiviral activity of the compounds disclosed has been attributed to selective phosphorylation by the HSV thymidine kinase and subsequent inhibition of the viral DNA polymerase (A Larsson et al., Antimicrob. Agents-Chemother., 30, 598-605 (1986).
Herpes simplex virus infections are currently best treated with acyclovir (ACV), which is a selective substrate for HSV thymidine kinase and (as the triphosphate) inhibits HSV DNA polymerase. ACV has been shown to be effective in treating primary herpes infections, but does not prevent establishment of latent infection.
Known antiviral agents, such as acyclovir, gancyclovir and BVDU, however, are susceptible to enzymatic phosphorylation in non-infected cells to a small extent and thus have an effect upon nucleotide pool sizes and, by means of DNA polymerase, can be incorporated into DNA, thus increasing mutagenicity hazards.
It was therefore an object of the present invention to identify novel, viral thymidine kinase (TK) inhibitory compounds which are not TK-substrates, but which might be effective in the prevention of viral reactivation or in the abolition of latency. Another object was to identify compounds which have utility and safety in the treatment of specific members of the herpes group (i.e., herpes simplex, types 1 and 2, and varicella zoster), which express their own thymidine kinases. A further object of the present invention was to identify pharmaceutical formulations for the effective administration of the novel compounds of the invention. Still another object is to provide methods for the preparation of the novel compounds of the present invention.